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Published on: December 1, 2023
Mitonuclear interactions influence multiple sclerosis risk
Maxim Kozin1, Olga Kulakova1, Ivan Kiselev1
1Pirogov Russian National Research Medical University, Moscow 117997, Russia.
Abstract:
Multiple sclerosis (MS) is a chronic disease of the central nervous system characterized by the autoimmune inflammation, demyelination, and neurodegeneration. This complex disease develops in genetically predisposed individuals under adverse environmental factors. To date, a large number of MS-associated polymorphic loci of the nuclear genome have been identified; however, their total variability can explain only about 48% of the observed inheritance of MS. Polymorphic variants of the mitochondrial genome and interactions of mitochondrial and nuclear genes (mitonuclear interactions) may be the possible sources of the "missing heritability". We analyzed the association with MS of 10 mitochondrial DNA polymorphisms (m.1719, m.4216, m.4580, m.4917, m.7028, m.9055, m.10398, m.12308, m.13368, m.13708) in DNA of 540 MS patients and 406 healthy individuals. The allele m.9055*G was the only mitochondrial variant associated with MS (Pf = 0.027). To evaluate interactions of mitochondrial and nuclear genomes, we searched for biallelic combinations containing one of 10 mitochondrial variants and one of 35 variants of immune-related nuclear genes. Carriership of mitochondrial variants m.4216, m.4580, or m.13708 in biallelic combinations with variants of nuclear genes IL7R, CLEC16A, CD6, CD86 or PVT1 was associated with MS (Pf = 0.0036-0.00030). We identified epistatic interaction between components of a combination (m.13708*A + PVT1 rs4410871*T). The existence of epistatic biallelic combination can reflect the genuine mitonuclear epistasis.
Insights
Mitochondrial DNA variants and their interactions with nuclear genes are linked to multiple sclerosis (MS) heritability. Specific mitochondrial variants, combined with nuclear gene variants, show significant associations with MS risk.
Area of Science:
- Genetics
- Neuroimmunology
- Mitochondrial Biology
Background:
- Multiple sclerosis (MS) is a complex central nervous system disease involving autoimmune inflammation, demyelination, and neurodegeneration.
- Genetic factors contribute significantly to MS heritability, but known nuclear genome variants explain only a portion of this inheritance.
- Mitochondrial DNA (mtDNA) polymorphisms and mitonuclear interactions are potential contributors to the 'missing heritability' in MS.
Purpose of the Study:
- To investigate the association of specific mitochondrial DNA polymorphisms with multiple sclerosis (MS).
- To explore the role of interactions between mitochondrial and nuclear genomes in MS susceptibility.
- To identify epistatic interactions between mitochondrial and nuclear genetic variants in MS.
Main Methods:
- Analysis of 10 mitochondrial DNA polymorphisms in 540 MS patients and 406 healthy controls.
- Examination of biallelic combinations between 10 mtDNA variants and 35 immune-related nuclear gene variants.
- Statistical analysis to assess associations and identify epistatic interactions.
Main Results:
- The mitochondrial variant m.9055*G was significantly associated with MS (Pf = 0.027).
- Specific combinations of mitochondrial variants (m.4216, m.4580, m.13708) with nuclear gene variants (IL7R, CLEC16A, CD6, CD86, PVT1) were associated with MS (Pf = 0.0036-0.00030).
- An epistatic interaction was identified between m.13708*A and PVT1 rs4410871*T, suggesting genuine mitonuclear epistasis.
Conclusions:
- Mitochondrial DNA variants contribute to MS susceptibility.
- Mitonuclear interactions, including epistatic effects, play a role in the genetic architecture of MS.
- These findings highlight the importance of considering both nuclear and mitochondrial genomes in understanding MS heritability.
